Diabetes is the most common cause of end stage kidney disease (ESKD) in the United States, accounting for ~40% of the cases of renal failure at the time of initiation of dialysis or transplantation. Moreover diabetic nephropathy (DN) is associated with markedly higher morbidity and mortality rates. These finding points to the role of chronic mild inflammation, increased ROS and endothelial dysfunction as playing central roles in renal pathogenesis of diabetic complications. Currently no new options for the treatment of DN have been forthcoming and treatment relies on the use of inhibitors of the renin angiotensin system. Novel therapeutic strategies are needed to prevent complications of diabetes. A2A -adenosine receptors are expressed in kidney as well as bone marrow (BM) derived cells and upon activation reduce inflammation. We have demonstrated that highly selective A2A -agonists reduce inflammation associated with acute renal ischemia-reperfusion injury (IRI) primarily by activating receptors on BM-derived cell. Moreover our preliminary data demonstrate that A2A -agonists have profound effects to reduce renal injury when administered chronically in a rat model of streptozotocin (STZ)-induced diabetes. Therefore we hypothesize that activating A2A adenosine receptors on bone marrow-derived cells ameliorates renal injury associated with diabetic nephropathy. Alternatively activation of A2A -ARs expressed on glomerular epithelial cells may reduce injury associated with diabetic nehpropathy. To this end: Aim 1 tests the hypothesis that A2A -agonists reduce renal functional and morphological consequences associated with diabetic nephropathy. Aim 2 tests the hypothesis that activation of A2A Rs on BM-derived cells mediates tissue protection. Aim 3 tests the hypothesis that activation of A2A Rs restores podocyte integrity in DN. Our experimental approach will use whole animals, genetically altered mice, cell culture and molecular biology to fully characterize the protective effect of A2A -agonists in DN as well as to define the cellular targets of A2A -agonists that are responsible for renal tissue protection in this disorder. This class of compounds has the potential to extent the use of anti-inflammatory A2A agonist therapy from acute uses that we have explored in the past, to more chronic uses where they may have great utility. These experiments also will shed light on the role of inflammation in the etiology of DN and provide insights into other potential anti-inflammatory therapeutic strategies.